β-amino-α-hydroxycarboxamides are important intermediates for chemical synthesis. They may, for example, be reacted further to 3-amino-2-ketamides. A multitude of recent protease inhibitors contain, as C-terminal units, 3-amino-2-ketoamides. Examples thereof are calpin inhibitors (WO 95/00535), thrombin inhibitors (J. Cacciola et al., Tetrahedron Lett. 38, 5741 (1997)) and, very particularly, a multitude of hepatitis C virus (HCV) protease inhibitors, as detailed, for example, in WO 05/087731, WO 05/058821. Among the latter, VX-950 is mentioned by way of example (WO 01/74768, WO 02/18369), which is already in advanced stages of clinical development.

The most commonly used process for preparing 3-amino-2-ketamides consists of the oxidation of the corresponding β-amino-α-hydroxycarboxamides:

For the preparation of these β-amino-α-hydroxycarboxamides, various processes are employed, which are listed hereinafter by way of example for 3-amino-2-hydroxyhexanoic acid:    1. Condensation of nitroalkanes with glyoxalic acid, reduction of the nitro group and subsequent conversion of the acid to the amide (K. X. Chen, J. Med. Chem. 49, 567, (2006); ibid. 995):

A disadvantage of this process is that the complete range of possible stereoisomeric compounds are obtained, which, after oxidation of the hydroxyl group, lead to mixtures of diastereomeric compounds, which cannot be separated in most cases. If they can, this is possible only with chromatographic methods (K. X. Chen, J. Med. Chem., 49, 995 (2006)).    2. Conversion of protected amino acids to the aldehydes, conversion to the cyanohydrins, hydrolysis thereof to the acid and subsequent conversion to the amides (e.g.: WO 01/74768, WO 02/18369, WO 05/087731, S.-H. Chen, Lett. Drug Design & Discovery, 2005, 118).

Disadvantages of this process are that the starting materials are expensive and mixtures of the diastereomeric amino alcohols are obtained, which can complicate isolation of intermediates in the synthesis steps which follow. Another disadvantage is that the free aminohydroxy acids are inevitably obtained, for whose conversion to the amides another introduction of an N-protecting group and generally an activation of the acid function are required.    3. By enantioselective aminohydroxylation (Sharpless, Angew, Chem. 109, 2752 (1997); WO 97/46516, WO 98/42657) of acrylic esters (WO 05/087731, US 2005/0197301):

A disadvantage of this process is that large amounts of chiral catalysts and toxic osmium oxide are required as oxidizing agents.    4. Primary amides can, by analogy to point 2, be prepared by reacting the aldehydes with isonitriles and acetic acid (J. G. Catalano, Biorg. Med. Chem. Lett., 14, 719 (2004); D. G. Barrett, ibid. 2543; L. Banfi, Molecular Diversity, 6, 227 (2003), WO 05/087731, US 2005/0197301):

In addition to the disadvantages mentioned under 2., an additional factor in this variant is that the isonitriles required are often not commercially available but rather have to be prepared in a complicated manner.    5. A further possibility consists in the regioselective ring opening of epoxyamides by means of azide and subsequent reduction to amino compounds (J. Cacciola, Tetrahedron Lett. 38, 5741 (1997); US 2003/0153788, K. B. Sharpless, J. Org. Chem. 50, 5696 (1985)).

A disadvantage of this variant is that azides have to be used for ring opening, which is problematic from a safety point of view, and an additional reduction step is required for conversion to the amines. For this process, it is also possible to use enantiomerically pure epoxides, which then directly afford a diastereomerically pure amino alcohol. For the preparation of enantiomerically pure epoxides, though, either the corresponding allyl alcohol has to be epoxidized according to Sharpless (J. Cacciola, Tetrahedron Lett. 38, 5741 (1997), US 2003/0153788) or, for the epoxidation of the corresponding acrylic acids, lanthanide complexes (T. Ohshima, Tetrahedron 59, 10485 (2003) have to be used. A direct asymmetric synthesis of epoxide amides is possible by reacting chiral S-alkylthioglycolamides with aldehydes (WO 03/08707).
It is also known that epoxycarboxylic acids and esters can be opened directly with ammonia or amines, preferably benzylamine. In this case, the free acids are opened exclusively by attack at the C-2 atom (e.g.: Y. Liwschitz, J. Chem. Soc., 1961, 1116). An exception is formed by 3-phenylglycidic acid, which reacts with ammonia predominantly to give phenylisoserine (WO 03/003804). Addition of at least stoichiometric amounts of Ti(O-iPr)4 in the reaction of aliphatic acids likewise allows a reversal of selectivity (K. B. Sharpless, J. Org. Chem. 50, 1560 (1985)). Esters, in contrast, are opened preferentially by attack on the C-3 atom (J. Chem. Soc. Perkin I, 1980, 1618). In this case, the esters are converted at least partly to the corresponding amides. A direct reaction of N-substituted epoxyamides with ammonia has to date not found any use, apparently because the amides range between the esters and the acids in the reactivity scale, and it would be expected that mixtures of 2- and 3-substituted aminohydroxamides would be obtained. In the case of reactions with ammonia, transamidations are additionally to be expected under the required reaction conditions. Therefore, the reaction with azides already described above has preferentially been employed.
While the reactions of beta-arylglycidic esters with ammonia and amines have been intensively examined (W. Tack, Arch. Pharm. 312, 138 (1979) and cit. lit; E. Kamandi, Arch. Pharm. 308, 135 (1975) and cit. lit., U.S. Pat. No. 6,025,516, WO 06/008170), little is known about the reaction of aliphatic glycidic esters.